WO2001019848A1 - Nouveaux procedes de production de composes peptidiques - Google Patents

Nouveaux procedes de production de composes peptidiques Download PDF

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Publication number
WO2001019848A1
WO2001019848A1 PCT/JP2000/006246 JP0006246W WO0119848A1 WO 2001019848 A1 WO2001019848 A1 WO 2001019848A1 JP 0006246 W JP0006246 W JP 0006246W WO 0119848 A1 WO0119848 A1 WO 0119848A1
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WO
WIPO (PCT)
Prior art keywords
compound
acid
salt
reaction
salts
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Application number
PCT/JP2000/006246
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English (en)
Japanese (ja)
Inventor
Masaharu Ichihara
Koji Machiya
Yasuhiro Morinaga
Nobutaka Kawai
Kazuo Ike
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP25974299A external-priority patent/JP2003171395A/ja
Priority claimed from JP28505999A external-priority patent/JP2003206299A/ja
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU73111/00A priority Critical patent/AU7311100A/en
Publication of WO2001019848A1 publication Critical patent/WO2001019848A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids

Definitions

  • the present invention provides a method for efficiently producing a heptide compound or a salt thereof having pharmacological activity such as tachykinin antagonism, in particular, substance P antagonism, neurokinin A antagonism, and neurokinin B antagonism in a small number of steps.
  • n peptide compound or a salt thereof obtained by this method is available for tachykinin-mediated diseases definitive in human or animal, for example, asthma, bronchitis, rhinitis, cough, respiratory diseases such as sputum; conjunctivitis, eye such as vernal Diseases: skin diseases such as pruritus, contact dermatitis, atopic dermatitis, urticaria, and other eczema-like dermatitis; inflammatory diseases such as rheumatoid arthritis and osteoarthritis; pain (for example, migraine, Useful for treating or preventing headache, toothache, cancer pain, back pain, etc.
  • the present applicant discloses a peptide compound represented by the following general formula (I) or a salt thereof as a compound useful as a tachykinin antagonist (Japanese Patent Application Laid-Open No. Hei 4210996) c
  • the above method is a general method for producing a peptide compound in which the peptide chain is extended by repeating protection and deprotection from the C-terminus, but the production is complicated due to the large number of steps (consisting of three steps). In addition, a recrystallization operation is required in the final step, and the yield of the target substance decreases throughout the entire process, which increases the production cost. In addition, methylene chloride is used as a reaction reagent, and there is an environmental problem. Replacement form (Rule 26) Therefore, there has been a long-felt need to provide a novel production method which can obtain the bebtide compound of the formula (I) in a smaller number of steps and in a higher yield. Problems to be solved by the invention
  • the present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a novel production method capable of obtaining a peptide compound or a salt thereof in a small number of steps with a high yield.
  • R ⁇ means an ar (lower) alkyl group] or a reactive derivative thereof or a salt thereof at an amino group, by the formula (II ⁇ ):
  • R 1 represents a lower alkyl group
  • R 1 represents a reactive derivative thereof or a salt thereof at a carboxy group
  • RR 2 and R : i have the same meanings as described above], respectively, and have the gist of obtaining a peptide compound or a salt thereof.
  • the starting compound UII is novel and can be produced by the production method described by the following reaction formula.
  • Suitable salts of the raw material compound and the target compound used in the present invention are conventional non-toxic salts, such as acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and formic acid.
  • Salts organic acid salts such as toluenesulfonate, for example, acid addition salts such as inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, or for example Salts with amino acids such as arginine, aspartic acid, glutamic acid, or sodium salt, potassium salt, etc.
  • Metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts; N, N'—Organic base salts such as dibenzylethylenediamine salt and the like.
  • lower unless otherwise indicated, the carbon atom 1 without, six teeth, preferably “lower alkyl group” c suitable to be intended and inter - mean four one-stone, methyl, Echiru, Purobiru And straight-chain or branched alkyl groups such as isopropyl, butyl, isobutyl, tertiary butyl, hentyl, hexyl, etc., the most preferred being the methyl group, the preferred "Al ( Examples of the “lower) alkyl group” include amino acids such as ar (lower) alkyl groups such as trityl, benzhydryl, benzyl, and r-netyl, and commonly used groups used in the field of chemical chemistry. Is mentioned.
  • Suitable “amino protecting groups” include the customary protecting groups used in the field of amino acid and peptide chemistry, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, octanolyl, isoxanolyl, vivaloyl And alkanoyl groups such as hexanoyl and the like, and acyl groups such as lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and tert-butoxycarbonyl.
  • the method for producing the target compound (I) of the present invention will be described in detail below.
  • the target compound)) or a salt thereof is produced by reacting the compound (II) or its reactive derivative at the amino group or its salt with the compound (III) or its reactive derivative at the carboxy group or its salt.
  • Suitable reactive derivatives at the amino group of compound (II) include Schiff's base imino or its enamine tautomer formed by the reaction of compound (II) with carbonyl compounds such as aldehydes and ketones.
  • Suitable reactive derivatives at the carboxy group of compound (III) include acid halides, acid anhydrides, activated amides, and the like.
  • Acid chloride acid azide; Substituted phosphoric acids such as alkylphosphoric acid, phenylphosphoric acid, difluorophosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid such as methanesulfonic acid, such as acetic acid Mixture with acids such as aliphatic carboxylic acids such as, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isobentanic acid, 2-ethylbutyric acid, trichloroacetic acid or aromatic carboxylic acids such as benzoic acid.
  • phosphoric acids such as alkylphosphoric acid, phenylphosphoric acid, difluorophosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, dialkylphosphorous acid, sulfurous acid, thiosul
  • These reactive derivatives are based on the type of compound UII) to be used. Can be arbitrarily selected from among them.
  • the reaction is usually carried out with water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine.
  • the reaction is carried out in a conventional solvent, but the reaction can be carried out in any other organic solvent which does not adversely affect the reaction.
  • These conventional solvents can be used as a mixture with water.
  • reaction may also involve the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri (lower) alkylamine, viridin, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine, etc. You may go down.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri (lower) alkylamine, viridin, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine, etc. You may go down.
  • the reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating.
  • the production method of the starting compound (III) is described in detail below.
  • Compound (III) or a salt thereof can be obtained by reacting compound (VII) or a reactive derivative thereof at the carboxy group or a salt thereof with compound (VIII) or a reactive derivative thereof at the imino group or a salt thereof.
  • compound (VII) or a reactive derivative thereof at the carboxy group or a salt thereof with compound (VIII) or a reactive derivative thereof at the imino group or a salt thereof.
  • This reaction can be carried out in substantially the same manner as in the production method of the above-mentioned compound (I). May be referred to.
  • the compound obtained by the above production method can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, etc.
  • Compound (1) and other compounds are It may contain one or more stereoisomers due to asymmetric carbon, and these isomers and mixtures thereof are all included in the scope of the present invention.
  • the present invention will be described in more detail with reference to Production Examples and Examples. Production Example 1
  • the reaction was performed sequentially, and the reaction was carried out at an internal temperature of 20 to 30 U C for about 2 hours.
  • ethyl acetate (320 1) and water (320 1) were added to the reaction solution, and the internal temperature was 2 ()-3 (stirred with TC, allowed to stand, and the organic layer was separated.
  • the organic layer was washed twice with 5% aqueous sodium bicarbonate (801), twice with 1N-hydrochloric acid (80) and water (801) while adding methanol (161) each time washing was performed.
  • the concentrated organic layer was concentrated to dryness under reduced pressure, dissolved again in ethyl acetate (240 1), concentrated to dryness under reduced pressure, and ethyl acetate (240 1) was added to the concentrated residue. After dissolving in C, the solution was cooled to an internal temperature of 20-30 V to precipitate crystals.
  • the internal temperature was cooled to 20 to 30 ° C.
  • the lysate was clarified and filtered through a 0.45 m membrane filter.
  • the dissolving tank and the non-blanc filter were washed with methanol (21 L).
  • the clarified filtrate and washing liquid are dropped into purified water (783 L), which has been adjusted to an internal temperature of 2 to 10 ° C in advance in a crystallization pot, and settled.
  • Replacement paper (Rule 26) After completion of the dropwise addition, the mixture was stirred at an internal temperature of 2 to ⁇ 0 ° C. for 30 minutes.
  • the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with an aqueous sodium hydrogen carbonate solution, water, 0.5 N hydrochloric acid, water and an aqueous sodium chloride solution, and dried over magnesium sulfate.
  • the residue is purified with a silica gel column (50 g), and the fraction containing the desired compound eluted with a mixed solvent of chloroform and methanol (50: ⁇ ) is collected and the solvent is collected.
  • R ′, R 2 and R : i each have the same meaning as before, and each represents an amino protecting group
  • the above-mentioned method is a general method for producing a peptide compound in which a peptide chain is extended by repeating protection and deprotection from the c-terminal, but the production is complicated due to the large number of steps (consisting of 6 steps). Not only that, a recrystallization operation is also required in the final step, and the yield of the target substance decreases throughout the entire process, increasing production costs.Methylene chloride is used as a reaction reagent. There are environmental issues. Therefore, it has been desired to provide a novel production method capable of obtaining the hebutide compound of the formula (1) with a smaller number of steps and in a high yield. Problems to be solved by the invention
  • the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a novel production method capable of obtaining a heftide compound or a salt thereof in a small number of steps with a high yield.
  • the manufacturing method of the present invention that solves the above-mentioned problem has a formula (I ⁇ )
  • R ′ has the same meaning as before, or a reactive derivative thereof at the carboxy group or a salt thereof, to obtain a compound of the formula (XII):
  • R 1 has the same meaning as before], or a salt thereof, and further a compound of the formula ( ⁇ V):
  • R ′, R 2 and R 3 have the same meanings as described above], and have the gist of obtaining a peptide compound or a salt thereof.
  • the starting compound (XI) is novel and can be produced by the production method described by the following reaction formula.
  • Suitable salts of the raw material compound and the target compound used in the present invention are conventional non-toxic salts, such as acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and the like.
  • Acid addition salts such as organic acid salts such as formate and toluenesulfonate, for example inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate, or For example, salts with amino acids such as arginine, asparaginic acid, and glutamic acid, or metal salts such as sodium salts and potassium salts, and calcium salts, and magnesium salts
  • Metal salts such as alkaline earth metal salts, such as metal salts, ammonium salts, for example, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine And organic base salts such as amine salts.
  • “Lower” shall mean from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • Replacement paper Kaikai IJ26
  • Suitable “lower alkyl groups” include straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropanol, butyl, isobutyl, tertiary butyl, benzyl, hexyl and the like.
  • c is methyl group "ar (lower) alkyl group", for example trityl, Benzuhi drill, benzyl, off; Oyo amino acid such as Al, such Nechiru (lower) alkyl And conventional groups used in the field of heptide chemistry.
  • Suitable “amino protecting groups” include those commonly used in the field of amino acid and peptide chemistry, such as, for example, formyl, acetyl, propionyl, petitinole, isobutyryl, octylinyl, and oxinylyl. Alkanol groups such as methoxy, ethoxycarbonyl, bromocarbonyl, butoxycarbonyl and tertiary butoxycarbonyl; and the like. Can be The method for producing the target compound (I) of the present invention will be described in detail below.
  • the target compound (1) or a salt thereof is obtained by reacting the compound ( ⁇ 1) or its reactive derivative at the amino group or its salt with the compound (XI) or its reactive derivative at the carboxy group or its salt.
  • the compound (XI 1) can be produced by further reacting the compound (XI 1) with the compound (IV) or a reactive derivative thereof at the amino group or a salt thereof.
  • Suitable reactive derivatives at the amino group of compound (I I) or compound (IV) include Schiff compounds formed by the reaction of compound (II) or compound (IV) with carbonyl compounds such as aldehydes and ketones.
  • silyl compounds such as compound (II) or compound (IV) and bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea, etc.
  • Suitable reactive derivatives at the carboxy group of compound (XI) include acid halides, acid anhydrides, activated amides, activated esters and the like.
  • Preferred examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, and halogenated phosphoric acid; and dialkylphosphorous acid.
  • Acid sulfurous acid, thiosulfuric acid, sulfuric acid, for example, sulfonic acid such as methanesulfonic acid, for example, acetic acid, propionic acid, butyric acid, isocyanic acid, hivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.
  • sulfonic acid such as methanesulfonic acid
  • Mixtures with aliphatic carboxylic acids or aromatic carboxylic acids such as benzoic acid, etc.
  • Acid anhydrides Symmetric acid anhydrides: with imidazole, 4-substituted imidazole, dimethylhirazol, triazole or tetrazole Activating amide; or for example cyanomethyl ester, methoxymethyl ester, dimethino remino Cyl ester, bier ester, propanoreginole ester, p-ditrophenyl ester, 2,4-dini trofeninoleestenole, triclo mouth fenenoreste / re, pentachlorophenyl enolenoestenole, mesinolephenyl enoestenole, feninoreazo Feninole ester, feninolethioestenole, p-2-trofeninolethioesterone, p-cresinolethioester, carboxymethinolethioesterone, viranyl ester, viridyl
  • These reactive derivatives can be arbitrarily selected from them according to the kind of the compound (X) to be used.
  • the reaction is usually carried out with water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl ethyl sulphate, N, N-dimethylformamide, pyridine If it is carried out in a conventional solvent such as that described above, but does not adversely affect the reaction, its replacement sheet (Rule 26) The reaction can be performed in any other organic solvent. These conventional solvents may be used as a mixture with water.
  • reaction it is desirable to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent.
  • a conventional condensing agent such as the so-called Vilsmeier reagent.
  • the reaction may also involve the presence of inorganic or organic bases such as alkali metal bicarbonates, tri (lower) alkylamines, pyridines, N- (lower) alkylmorpholines, N, N-di (lower) alkylbenzylamines, etc. Go down, c .
  • the reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating.
  • the method for producing the starting compound (III) will be described in detail below.
  • Replacement form (Rule 26) Compound (I 1 ⁇ ) or a salt thereof is obtained by combining compound (VII) or a reactive derivative thereof at the carboxy group or a salt thereof with compound (VI 1 I) or a reactive derivative thereof at the imino group or a salt thereof.
  • Suitable salts of the compound (VII) and the compound (VIII) which can be produced by the reaction can be referred to those exemplified for the compound (1).
  • This reaction can be carried out in substantially the same manner as in the production of the compound U) .
  • the reaction scheme of the reaction and the reaction conditions such as, for example, the reactive derivative, the solvent, the reaction temperature, etc. the reference to the production method described Surebayore, c. compound obtained by the above process, the milling, recrystallization, column chromatography I over, isolated by conventional methods such as reprecipitation, purifying Can be.
  • Compound (I) and other compounds may contain one or more stereoisomers due to asymmetric carbon, and these isomers and mixtures thereof are all included in the scope of the present invention.
  • the present invention will be described in more detail with reference to Production Examples and Examples.
  • aqueous layer is then acidified with 6N hydrochloric acid to ⁇ 2, extracted with ethyl acetate, the extract is washed with aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. Crystallize from a mixed solvent of diisopropyl ether and ⁇ -hexane, collect by filtration and dry
  • N-tert-butoxycarbonyl-3- (2-naphthyl) -l-alanine (1.34 g)
  • N-methylbenzylamine (0.49 ml)
  • N-hydroxybenzotriazole (0.95 g).
  • ethyl 3- (3'-dimethylaminobutyl pill) carbodiimide 'hydrochloride (0.95 g). The solution is stirred for 1 hour at the same temperature and overnight at room temperature.
  • the reaction mixture is extracted with ethyl acetate, and the organic layer is washed successively with water, an aqueous solution of sodium hydrogen carbonate, 0.5 N hydrochloric acid, water and an aqueous solution of sodium chloride, and dried over magnesium sulfate.
  • the solvent was distilled off to obtain N 2 -tert-butoxycarbonyl-N-benzyl-N-methyl-3- (2-naphthyl) -L-alanine amide (1.74 g) as an oil.
  • N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide hydrochloride (1.5 g), 1-primary tert-butoxycarboryl (4R) — 4-hydroxyl-L-proline (0.98 g) and hydroxybenzotriazole (0.57 g) in a mixed solvent of methylene chloride (40 ml) and dimethylformamide (5 ml) in an ice-cold solution were mixed with N-ethyl- ⁇ '. — (3-Dimethylaminobu pill) carbodiimid (0.77 ml) was added. The solution was stirred at the same temperature for 1 hour and at room temperature overnight.
  • the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with an aqueous solution of sodium hydrogen carbonate, water, 0.5 N hydrochloric acid, water and an aqueous solution of sodium chloride, and dried over magnesium sulfate.
  • the residue is purified by a silica gel column (50 g) and eluted with a mixed solvent of chloroform and methanol (50: 1). Fractions containing the desired compound were collected and the solvent was distilled off.
  • the production method of the present invention is configured as described above and has a tachykinin antagonism.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Biochemistry (AREA)
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  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne de nouveaux procédés industriels de production de composés peptidiques (I). Plus particulièrement, un procédé de production de composés peptidiques de formule générale (I) ou de sels de ceux-ci: (où R1 est alkyle inférieur; R2 est alkyle inférieur; et R3 est ar alkyle (inférieur)) en faisant réagir un composé de formule générale (II) ou un dérivé réactif formé à partir de celui-ci par modification du groupe aminé ou d'un sel de celui-ci avec un composé de formule générale (III) ou un dérivé réactif formé à partir de celui-ci par modification du groupe carboxyle ou d'un sel de celui-ci et un autre procédé de production de composés peptidiques de formule générale (I) ou de sels de ceux-ci, en faisant réagir un composé de formule générale (IV) ou un dérivé réactif formé à partir de celui-ci par modification du groupe carboxyle ou d'un sel de celui-ci avec un composé de formule générale (V) ou un dérivé réactif formé à partir de celui-ci par modification du groupe aminé ou d'un sel de celui-ci.
PCT/JP2000/006246 1999-09-14 2000-09-13 Nouveaux procedes de production de composes peptidiques WO2001019848A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73111/00A AU7311100A (en) 1999-09-14 2000-09-13 Novel processes for the production of peptide compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP11/259742 1999-09-14
JP25974299A JP2003171395A (ja) 1999-09-14 1999-09-14 ペプチド化合物の新規製造法
JP11/285059 1999-10-06
JP28505999A JP2003206299A (ja) 1999-10-06 1999-10-06 ペプチド化合物の新規製造法

Publications (1)

Publication Number Publication Date
WO2001019848A1 true WO2001019848A1 (fr) 2001-03-22

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WO (1) WO2001019848A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021215A1 (fr) * 1992-04-21 1993-10-28 Fujisawa Pharmaceutical Co., Ltd. Peptides ayant une action antagoniste de la tachykinine
WO1995000536A1 (fr) * 1993-06-22 1995-01-05 Fujisawa Pharmaceutical Co., Ltd. Compose a base de peptides
JPH08325300A (ja) * 1995-06-01 1996-12-10 Konica Corp カルボキシル基含有低分子化合物の結合方法及び結合用キット

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021215A1 (fr) * 1992-04-21 1993-10-28 Fujisawa Pharmaceutical Co., Ltd. Peptides ayant une action antagoniste de la tachykinine
WO1995000536A1 (fr) * 1993-06-22 1995-01-05 Fujisawa Pharmaceutical Co., Ltd. Compose a base de peptides
JPH08325300A (ja) * 1995-06-01 1996-12-10 Konica Corp カルボキシル基含有低分子化合物の結合方法及び結合用キット

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